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Analysis of the Gene Coding for Steroidogenic Factor 1 (SF1, NR5A1) in a Cohort of 50 Egyptian Patients with 46,XY Disorders of Sex Development

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Analysis of the Gene Coding for Steroidogenic Factor 1 (SF1, NR5A1) in a Cohort of 50 Egyptian Patients with 46,XY Disorders of Sex Development S Tantawy and others SF1 in Egyptians with 46,XY DSD 170:5 759–767 Clinical Study Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development Sally Tantawy1,2, Inas Mazen2, Hala Soliman3, Ghada Anwar4, Abeer Atef4, Mona El-Gammal2, Ahmed El-Kotoury2, Mona Mekkawy5, Ahmad Torky2, Agnes Rudolf1, Pamela Schrumpf1, Annette Gru¨ ters1, Heiko Krude1, Marie-Charlotte Dumargne6, Rebekka Astudillo1, Anu Bashamboo6, Heike Biebermann1 and Birgit Ko¨ hler1 1Institute of Experimental Paediatric Endocrinology, University Children’s Hospital, Charite´ , Humboldt University, Correspondence Berlin, Germany, 2Department of Clinical Genetics and 3Department of Medical Molecular Genetics, Division of should be addressed Human Genetics and Genome Research, National Research Centre, Cairo, Egypt, 4Department of Paediatrics, to S Tantawy Cairo University, Cairo, Egypt, 5Department of Cytogenetics, Division of Human Genetics and Genome Research, Email National Research Centre, Cairo, Egypt and 6Human Developmental Genetics, Institut Pasteur, Paris, France [email protected] Abstract Objective: Steroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamic– pituitary–gonadal axis. Recently, SF1 mutations were found to be a frequent cause of 46,XY disorders of sex development (DSD) in humans. We investigate the frequency of NR5A1 mutations in an Egyptian cohort of XY DSD. Design: Clinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum. Methods: Molecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the European Journal of Endocrinology two novel missense mutations detected. Results: Three novel heterozygous mutations of the coding region in patients with hypospadias were detected. p.Glu121AlafsX25 results in severely truncated protein, p.Arg62Cys lies in DNA-binding zinc finger, whereas p.Ala154Thr lies in the hinge region of SF1 protein. Transactivation assays using reporter constructs carrying promoters of anti-Mu¨ llerian hormone (AMH), CYP11A1 and TESCO core enhancer of Sox9 showed that p.Ala154Thr and p.Arg62Cys mutations result in aberrant biological activity of NR5A1. A total of 17 patients (34%) harboured the p.Gly146Ala polymorphism. Conclusion: We identified two novel NR5A1 mutations showing impaired function in 23 Egyptian XY DSD patients with hypospadias (8.5%). This is the first study searching for NR5A1 mutations in oriental patients from the Middle East and Arab region with XY DSD and no adrenal insufficiency, revealing a frequency similar to that in European patients (6.5–15%). We recommend screening of NR5A1 in patients with hypospadias and gonadal dysgenesis. Yearly follow-ups of gonadal function and early cryoconservation of sperms should be performed in XY DSD patients with NR5A1 mutations given the risk of future fertility problems due to early gonadal failure. European Journal of Endocrinology (2014) 170, 759–767 www.eje-online.org Ñ 2014 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-13-0965 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 04:16:59AM via free access Clinical Study S Tantawy and others SF1 in Egyptians with 46,XY DSD 170:5 760 Introduction Subjects and methods Disorders of sex development (DSDs) are complex Cohort disorders with atypical chromosomal, gonadal or ana- A cohort of 50 Egyptian 46,XY DSD patients were recruited tomical sex (1). DSDs are classified into three groups: from the Pediatric Endocrinology Clinic of Cairo i) DSD with numerical sex chromosomal aberrations, University and the Clinical Genetics and Endocrinology ii) XY DSD and iii) XX DSD. Sex chromosome DSD Departments of National Research Centre (NRC) in Cairo, consists mainly of disorders with gonadal dysgenesis due Egypt. Patients’ chronological ages ranged from 2 months to sex chromosome imbalances such as Turner syndrome to 33 years at first presentation. The phenotypic spectrum (45,X and mosaicism), Klinefelter syndrome (47,XXY), included complete female external genitalia with/without mixed gonadal dysgenesis (45,X0/46,XY) and chimeric uterus (nZ8), ambiguous genitalia without uterus (nZ5), DSD (46,XX/46,XY). XY DSD comprises mainly testicular vanishing/atrophic testes (nZ10), hypospadias with nor- dysgenesis, defects of androgen synthesis or action and mally descended testis (nZ9), hypospadias with at least hypospadias. XX DSD includes congenital adrenal one undescended testis (nZ14) and isolated hypoplastic hyperplasia, ovarian dysgenesis and uterine/vaginal nZ malformations (1). In Egypt, the occurrence of DSD is phallus ( 4). Patients with syndromic forms of gonadal rare with an incidence of 1:5000 (2) similar to 1:4500 dysgenesis or chromosomal abnormalities were excluded. worldwide (3). In Egypt, 46,XY DSD constitutes the Among the 50 patients, 39 were reared as males, 11 as majority of DSD cases (65.9%) (4) with androgen females and one was reared as female at birth then her sex insensitivity syndrome and 5-a-reductase deficiency was changed to male at 2 years of age. Written informed being the two most frequent 46,XY DSD aetiologies due consent for genetic analysis was obtained according to to high consanguinity. They constitute 64% among all institutional ethical guidelines from the patients and/or reported cases (5). However, in many cases the patho- their parents. genetic cause is unknown. Work-up included cytogenetic analysis by G-banding During the last 10 years, steroidogenic factor 1 (SF1, technique in 50 metaphases (20), and pelviabdominal NR5A1) has been found to play a pivotal role in human sex ultrasound. Testosterone, precursors and dihydrotesto- differentiation. SF1 is a key transcriptional regulator of sterone (DHT) were measured before and after human many genes involved in the hypothalamic–pituitary– chorionic gonadotropin (hCG) stimulation. In some cases, gonadal axis and adrenal cortex (6). Sf1 null mice pelvic laparoscopy, biopsy and histological analysis of the European Journal of Endocrinology demonstrate complete gonadal dysgenesis and adrenal gonads were performed. failure (7). However, humans harbouring heterozygous NR5A1 mutations display a milder phenotype. The Molecular analysis of NR5A1 gene majority of cases display 46,XY DSD with ambiguous genitalia or hypospadias due to partial gonadal dysgenesis Molecular analysis of exons 2–7 of the gene encoding SF1 but no adrenal insufficiency. To date, about 60 different (NR5A1) was performed as described previously (21). NR5A1 mutations have been reported in humans with Numbering of the mutations is based on GenBank reference DSDs. So far, there is no apparent genotype–phenotype DNA sequence NM_004959.4, with the A of the ATG correlation in patients with NR5A1 mutations. initiation codon designated C1(www.hgvs.org/mutnomen). The phenotypic spectrum has been extended, involving A total of 100 Egyptian controls (200 alleles) were not only ambiguous genitalia and hypospadias due to sequenced for both the mutations and the single- gonadal dysgenesis (8, 9, 10), but also vanishing testis nucleotide polymorphisms (SNPs). syndrome (11), isolated hypoplastic penis (12) and male infertility (13, 14). Moreover, NR5A1 mutations were also Functional analysis found in 46,XX females with premature ovarian failure and primary ovarian insufficiency (15, 16, 17, 18, 19). Vector containing full-length mouse Nr5a1,pCNA3- Altogether, NR5A1 mutations have emerged as being the NR5A1-myc and the mouse TESCO reporter were a gift most frequent cause (6.5–15%) of different phenotypes of from Dr Francis Poulat, Institut de Ge´ne´tique Mole´culaire 46,XY DSD in Western countries. Our aim is to investigate de Montpellier. The reporters containing the minimal whether NR5A1 mutations are also a cause of 46,XY DSD anti-Mu¨llerian hormone (AMH) and CYP11A1 promoters in Egypt. (K269) are described previously (17). www.eje-online.org Downloaded from Bioscientifica.com at 09/27/2021 04:16:59AM via free access Clinical Study S Tantawy and others SF1 in Egyptians with 46,XY DSD 170:5 761 A R62CR62C hypospadias: heterozygous p.Arg62Cys (c.184 COT), HumanHuman E S Q S C K I D K T Q R K R C P F C R F Q K C L heterozygous p.Glu121AlafsX25 (c.361delGAGACAGG) MutatedMutated Q C K R C P F C R F Q K C and heterozygous p.Ala154Thr (c.460 GOA) (Figs 1 ChimpChimp E S Q S C K I D K T Q R K R C P F C R F Q K C and 2). No NR5A1 mutations were found in patients RhesusRhesus Q R K R C P F C R F Q K C with other phenotypes such as complete gonadal dysgen- MouseMouse Q R K R C P F C R F Q K C esis, isolated micropenis or vanishing/atrophic testes. XenopusXenopus Q R K R C P Y C R F Q K C ElegansElegans A E A N C H V D R T C R K R C P S C R F The consanguinity rate among parents of all included DrosophilaDrosophila A E R S C H I D K T Q R K R C P Y C R 46,XY DSD patients in our study was 53%, where 34% were first cousins and 19% were second cousins or further relatives. In Egypt, the rate of total consanguineous A154TA154T B marriages was 29.7% in 2008 (22) and reached 35.3% in HumanHuman S L H G P E P K G L A A G P P A G P L G D F G A 2011 (23). MutatedMutated S L H G P E P K G L A T G P P A G P L G D F G ChimpChimp S L H A P E P K G L A A G P P A G P L G D F G RhesusRhesus S L H A P E P K G L A A G P P T G P L G D F G Case histories MouseMouse S L H A P E P K A L V S G P P S G P L G D F G XenopusXenopus N I H T I H PVTPVT K N L P P N PAPAP M T P VEYDRVEYDR G P Y G Patient 1 (p.Arg62Cys) " Patient 1 is a 1 six and a half- DrosophilaDrosophila E I Q I P Q V S S L T Q S P D S S P year-old male, born to non-consanguineous parents, presenting with severely hypoplastic phallus (stretched Figure 1 penile length was 1 cm, !K2.5 SDS), penile hypospadias, (A) The mutated arginine residue in position 62 is highly hypoplastic scrotum and impalpable gonads.
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